biostudies-literatureGao JMFundamental Research Funds for the Central Universities"'hundred"' level of high-level innovative talents in Guizhou ProvinceNational Natural Science Foundation of ChinaCentral Government-Guided Local S&T Special Project of Guizhou Provincee11611https://www.ebi.ac.uk/biostudies/studies/S-EPMC12631941biostudies-literatureUnknown12(43)The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging reaAdvanced science (Weinheim, Baden-Wurttemberg, Germany)A Single-Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration.PMC1263194122371147GCC[2023]04222201141[2025]030Pan YCLi WBYuan ZLYi YGuo DSZhao YYGong QHChen NNGao JWang ZHChen XGao JMfalseA Single-Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration.The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging rea2025-01-01T00:00:00Z2025 Nov2026-06-05T17:32:01.543Z2026-06-05T03:07:38.42ZS-EPMC126319414085993010.1002/advs.202511611